Project Summary: Herpes simplex virus type 1 (HSV-1) corneal infections are a leading infectious cause of blindness world-wide. It is well established that the blinding form of HSV-1 infection called herpes stromal keratitis (HSK) is caused by the immune response to the virus rather than by a direct effect of the virus on corneal cells. The disease tends to recur in people because the virus invades and establishes a quiescent (latent) infection in sensory nerves during initial (primary) infection. HSV-1 periodically reactivates from the latent state, travels back down the nerves to the cornea, and triggers recurrent bouts of HSK. A hallmark of HSK is loss of corneal sensitivity that has been associated with loss of corneal sensory nerve endings. However, the relationship between neuronal changes in infected corneas and the pathogenesis of HSK has not been well studied. Our preliminary studies in mice demonstrated that sympathetic nerves invade the cornea when sensory nerves are lost, and sympathetic nerves play a key role in the activation of immune cells and their contribution to HSK. Our proposed studies will explore the mechanisms of this neuro-immune interaction. Our first aim will determine the mechanisms responsible for sympathetic nerve invasion of the cornea, expanding on our preliminary finding that these nerves fail to invade infected corneas when CD4+ T lymphocytes or macrophages are depleted from the host animal. Our second aim will determine the mechanism by which sympathetic nerves induce severe inflammation in infected corneas, by expanding on current knowledge that the catecholamines produced by sympathetic nerves (but not by sensory nerves) can stimulate macrophages and CD4 T lymphocytes to produce inflammatory mediators of HSK. In people it appears that loss of corneal sensory nerves and corneal sensation is a gradual process that progresses with serial HSK recurrences and is associated with increasingly severe HSK. Our third aim will attempt for the first time to induce serial HSK recurrences in mice and determine if sensory nerve loss and sympathetic nerve innervation progress with serial recurrences. We predict an increasing role for sympathetic nerves and catecholamines with recurrences of HSK in mice. Our studies will define a whole new neuro-immune component of HSK and in so doing provide new avenues of intervention in this blinding disease.